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Drugs

, Volume 64, Issue 11, pp 1181–1196 | Cite as

Medical Lipid-Regulating Therapy

Current Evidence, Ongoing Trials and Future Developments
Review Article

Abstract

Coronary heart disease (CHD) is a major cause of morbidity and mortality worldwide. Elevated low density lipoprotein-cholesterol (LDL-C) and reduced high density lipoprotein-cholesterol (HDL-C) levels are well recognised CHD risk factors, with recent evidence supporting the benefits of intensive LDL-C reduction on CHD risk. Such observations suggest that the most recent National Cholesterol Education Program Adult Treatment Panel III guidelines, with LDL-C targets of 2.6 mmol/L, may result in under-treatment of a significant number of patients and form the basis for the proposed new joint European Societies treatment targets of 2 and 4 mmol/L, respectively, for LDL and total cholesterol. HMG-CoA reductase inhibitors (statins) reduce LDL-C by inhibiting the rate-limiting step in cholesterol biosynthesis and reduced CHD event rates in primary and secondary prevention trials. The magnitude of this effect is not fully accounted for by LDL-C reduction alone and may relate to effects on other lipid parameters such as HDL-C and apolipoproteins B and A-I, as well as additional anti-inflammatory effects. With increasing focus on the benefits of intensive cholesterol reduction new, more efficacious statins are being developed. Rosuvastatin is a potent, hydrophilic enantiomeric statin producing reductions in LDL-C of up to 55%, with about 80% of patients reaching European LDL-C treatment targets at the 10 mg/day dosage.

The Heart Protection Study (HPS) demonstrated that LDL-C reduction to levels as low as 1.7 mmol/L was associated with significant clinical benefit in a wide range of high-risk individuals, including patients with type 2 diabetes mellitus, or peripheral and cerebrovascular disease, irrespective of baseline cholesterol levels, with no apparent lower threshold for LDL-C with respect to risk. Various large endpoint trials, including Treating to New Targets (TNT) and Study of Effectiveness of Additional reductions in Cholesterol and Homocysteine (SEARCH) will attempt to further address the issue of optimal LDL-C reduction. At low LDL-C levels, HDL-C becomes an increasingly important risk factor and is the primary lipid abnormality in over half of CHD patients, with the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study set to assess the effect of raising HDL-C on cardiovascular events in patients with low HDL-C and LDL-C levels below 3 mmol/L.

A variety of agents are being developed, which affect both LDL-C and HDL-C metabolism, including inhibitors of acyl-coenzyme A-cholesterol acyl transferase, microsomal transfer protein and cholesterol ester transfer protein, as well as specific receptor agonists. Ezetimibe is a selective cholesterol absorption inhibitor, which produces reductions in LDL-C of up to 25 and 60% reduction in chylomicron cholesterol content with a 10 mg/day dosage.

A 1 mmol/L reduction in LDL-C results in a 25% reduction in cardiovascular risk, independent of baseline LDL-C levels. Growing evidence supports the concept that lower is better for LDL-C and that increasing HDL-C represents an important therapeutic target. Furthermore, there is growing appreciation of the role of inflammation in atherogenesis. Consequently, increasing numbers of people should receive lipid-regulating therapy with the development of newer agents offering potential mechanisms of optimising lipid profiles and thus risk reduction. In addition, the pleiotropic anti-inflammatory effects of lipid lowering therapy may provide further risk reduction.

Keywords

Statin Therapy Ezetimibe Coronary Heart Disease Risk Cholesteryl Ester Transfer Protein Microsomal Triglyceride Transfer Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The authors have no conflicts of interest directly relevant to the content of this review. The authors have provided no information on sources of funding directly relevant to the content of this review.

References

  1. 1.
    American Heart Association. 2001 heart and stroke statistical update. Dallas (TX): American Heart Association, 2001Google Scholar
  2. 2.
    Kannel WB, Larson M. Long-term epidemiologic prediction of coronary disease: the Framingham experience. Cardiology 1993; 82(2–3): 137–52PubMedGoogle Scholar
  3. 3.
    Stamler J, Daviglus ML, Garside DB, et al. Relationship between baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular and all cause mortality and longevity. JAMA 2000; 284(3): 311–8PubMedGoogle Scholar
  4. 4.
    Vogel RA. Coronary risk factors, endothelial function and atherosclerosis: a review. Clin Cardiol 1997; 54(1): 1–8Google Scholar
  5. 5.
    Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801–9PubMedGoogle Scholar
  6. 6.
    Scandinavian Simvastatin Survival Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–9Google Scholar
  7. 7.
    Shepeherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolaemia: West of Scotland coronary prevention study. N Engl J Med 1995; 333(20): 1301–7Google Scholar
  8. 8.
    Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high risk individuals: a randomised placebo controlled trial. Lancet 2002; 360: 7–22Google Scholar
  9. 9.
    Jacobs D, Blackburn H, Higgins M, et al. Report of the conference on low blood cholesterol: mortality associations. Circulation 1992; 86: 1040–60Google Scholar
  10. 10.
    Stamler J, Vaccaro O, Neaton JD, et al. Diabetes, other risk factors and 12-year cardiovascular mortality for men screened in the multiple risk factor intervention trial. Diabetes Care 1993; 16: 343–4Google Scholar
  11. 11.
    The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of cholesterol levels. N Engl J Med 1998; 338: 1349–57Google Scholar
  12. 12.
    Downs JR, Clearfiled M, Weis S, et al., for the AFCAPS/ TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA 1998; 279: 1615–22PubMedGoogle Scholar
  13. 13.
    Sacks FM, Pfeffer MA, Moye LA, et al., for the Cholesterol and Recurrent Events Trial investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001–9PubMedGoogle Scholar
  14. 14.
    Genest JJ, McNamara JR, Ordovas JM, et al. Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary heart disease. J Am Coll Cardiol 1992; 19: 792–802PubMedGoogle Scholar
  15. 15.
    Chen Z, Peto R, Collins R, et al. Serum cholesterol concentration and coronary heart disease in a population with low cholesterol levels. BMJ 1991; 303: 276–82PubMedGoogle Scholar
  16. 16.
    Verschuuren WM, Jacobs DR, Bloemberg BP, et al. Serum total cholesterol and long-term coronary heart disease mortality in different culture: twenty five year follow up of the seven countries study. JAMA 1995; 274: 131–6Google Scholar
  17. 17.
    Assman G, Cullen P, Schulte H. The Munster Heart study (PROCAM): results of follow up at 8 years. Eur Heart J 1998; 19 Suppl. A: A2–A11Google Scholar
  18. 18.
    Wilson PW, Anderson KM, Castelli WP. Twelve year incidence of CHD in middle aged adults during the era of hypertensive therapy. The Framingham offspring study. Am J Med 1991; 90: 276–82Google Scholar
  19. 19.
    Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Programme (NCEP) expert panel on detection evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001; 285: 2486–97Google Scholar
  20. 20.
    Wood D, De Backer G, Faegerman O, et al. Prevention of coronary heart disease in clinical practice: recommendations of the second joint task force of European and other societies on coronary prevention. Eur Heart J 1998; 19: 1434–503Google Scholar
  21. 21.
    Serruys PWJC, De Feyter P, Macaya N, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention. JAMA 2002; 287: 3215–22PubMedGoogle Scholar
  22. 22.
    Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischaemic events in acute coronary syndromes: The MIRACL study: a randomized controlled trial. JAMA 2001; 285(13): 1711–8PubMedGoogle Scholar
  23. 23.
    Smilde TJ, van Wissen S, Wollersheim H, et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001; 357(9256): 577–81PubMedGoogle Scholar
  24. 24.
    Taylor AJ, Kent SM, Flaherty PJ, et al. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation 2002; 106(16): 2055–60PubMedGoogle Scholar
  25. 25.
    The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The antihypertensive and lipid-lowering treatment to prevent heart attack trial: major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002; 288(23): 2998–3007Google Scholar
  26. 26.
    Deanfield JE. Clinical trials: evidence and unanswered questions: hyperlipidaemia. Cerebrovasc Dis 2003; 16 Suppl. 3: 25–32PubMedGoogle Scholar
  27. 27.
    MacMahon M, Kirkpatrick C, Cummings CE, et al. A pilot study with simvastatin and folic acid/vitamin B12 in preparation for the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH). Nutr Metab Cardiovasc Dis 2000 Aug; 10(4): 195–203PubMedGoogle Scholar
  28. 28.
    Raggi P, Callister TQ, Davidson M, et al. Aggressive versus moderate lipid-lowering therapy in postmenopausal women with hypercholesterolemia: rationale and design of the Beyond Endorsed Lipid Lowering with EBT Scanning (BELLES) trial. Am Heart J 2001; 141(5): 722–6PubMedGoogle Scholar
  29. 29.
    Waters DD, Guyton JR, Herrington DM, et al.; TNT Steering Committee Members and Investigators. Treating to New Targets (TNT) study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit? Am J Cardiol 2004 Jan 15; 93(2): 154–8PubMedGoogle Scholar
  30. 30.
    Cannon CP. The next step in cardiovascular protection. Atheroscler Suppl 2003 Dec; 4(5): 3–9PubMedGoogle Scholar
  31. 31.
    Assman G. Pro and con: high-density lipoprotein, triglycerides and other lipid sub-fractions are the future of lipid management. Am J Cardiol 2001; 87 Suppl. 2: 2B-7BGoogle Scholar
  32. 32.
    Despres JP. Increasing high-density lipoprotein cholesterol: an update on fenofibrate. Am J Cardiol 2001; 88(12A): 30N–6NPubMedGoogle Scholar
  33. 33.
    Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001; 103: 357–62PubMedGoogle Scholar
  34. 34.
    Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287: 356–9PubMedGoogle Scholar
  35. 35.
    The International Taskforce for the prevention of coronary heart disease. Coronary heart disease: reducing the risk. Nutr Metab Cardiovasc Dis 1998; 8: 205–71Google Scholar
  36. 36.
    Robins SJ, Collins D, Wittes JT, et al., VA-HIT Study Group. Veterans affairs high-density lipoprotein intervention trial: relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA 2001 Mar 28; 285(12): 1585–91PubMedGoogle Scholar
  37. 37.
    Gotto Jr AM, Whitney E, Stein EA, et al. Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 2000; 101(5): 477–84PubMedGoogle Scholar
  38. 38.
    Rashid S, Uffelman KD, Barrett PH, et al. Effect of atorvastatin on high-density lipoprotein apolipoprotein A-I production and clearance in the New Zealand white rabbit. Circulation 2002; 106(23): 2955–60PubMedGoogle Scholar
  39. 39.
    Duriez P. Mechanisms of actions of statins and fibrates [in French]. Therapie 2003; 58(1): 5–14PubMedGoogle Scholar
  40. 40.
    Kotake H, Sekikawa A, Tokita Y, et al. Effect of HMG-CoA reductase inhibitor on plasma cholesteryl ester transfer protein activity in primary hypercholesterolemia: comparison among CETP/TaqIB genotype subgroups. J Atheroscler Thromb 2002; 9(5): 207–12PubMedGoogle Scholar
  41. 41.
    Tailleux A, Duriez P, Fruchart JC, et al. Apolipoprotein A-II, HDL metabolism and atherosclerosis. Atherosclerosis 2002; 164(1): 1–13PubMedGoogle Scholar
  42. 42.
    Vosper H, Khoudoli GA, Graham TL, et al. Peroxisome proliferator-activated receptor agonists, hyperlipidaemia, and atherosclerosis. Pharmacol Ther 2002; 95(1): 47–62PubMedGoogle Scholar
  43. 43.
    Kreisberg RA. Diabetic dyslipidemia. Am J Cardiol 1998; 82(12A): 67U–73UPubMedGoogle Scholar
  44. 44.
    The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation 2000; 102: 21–7Google Scholar
  45. 45.
    The DAIS Study Group. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 2001; 357(9260): 905–10Google Scholar
  46. 46.
    Lu W, Resnick HE, Jablonski KA, et al. Non-HDL cholesterol as a predictor of cardiovascular disease in type 2 diabetes: the strong heart study. Diabetes Care 2003; 26(1): 16–23PubMedGoogle Scholar
  47. 47.
    Frost PH, Davis BR, Burlando AJ, et al. Serum lipids and incidence of coronary heart disease: findings from the Systolic Hypertension in the Elderly Program (SHEP). Circulation 1996; 94(10): 2381–8PubMedGoogle Scholar
  48. 48.
    Cui Y, Blumenthal RS, Flaws JA, et al. Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality. Arch Intern Med 2001; 161(11): 1413–9PubMedGoogle Scholar
  49. 49.
    Libby P. Inflammation in atherosclerosis. Nature 2002; 420(6917): 868–74PubMedGoogle Scholar
  50. 50.
    Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001; 285(19): 2481–5PubMedGoogle Scholar
  51. 51.
    Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002; 347(20): 1557–65PubMedGoogle Scholar
  52. 52.
    Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein: the Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999; 100(3): 230–5PubMedGoogle Scholar
  53. 53.
    Ridker PM, Rifai N, Clearfield M, et al., Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001; 344(26): 1959–65PubMedGoogle Scholar
  54. 54.
    Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105(9): 1135–43PubMedGoogle Scholar
  55. 55.
    Yamamoto Y, Gaynor RB. Role of the NF-kappaB pathway in the pathogenesis of human disease states. Curr Mol Med 2001; 1(3): 287–96PubMedGoogle Scholar
  56. 56.
    Durrington PN, Mackness B, Mackness MI. Paraoxonase and atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21(4): 473–80PubMedGoogle Scholar
  57. 57.
    Weitz-Schmidt G. Statins as anti-inflammatory agents. Trends Pharmacol Sci 2002; 23(10): 482–6PubMedGoogle Scholar
  58. 58.
    Liuzzo G, Baisucci LM, Gallimore JR, et al. Enhanced inflammatory response in patients with preinfarction unstable angina. J Am Coll Cardiol 1999; 34(6): 1696–703PubMedGoogle Scholar
  59. 59.
    Daynes RA, Jones DC. Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol 2002; 2(10): 748–59PubMedGoogle Scholar
  60. 60.
    Delerive P, Gervois P, Fruchart JC, et al. Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J Biol Chem 2000; 275(47): 36703–7PubMedGoogle Scholar
  61. 61.
    Delerive P, De Bosscher K, Besnard S, et al. Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J Biol Chem 1999; 274(45): 32048–54PubMedGoogle Scholar
  62. 62.
    Duval C, Chinetti G, Trottein F, et al. The role of PPARs in atherosclerosis. Trends Mol Med 2002; 8(9): 422–30PubMedGoogle Scholar
  63. 63.
    Wang N, Verna L, Chen NG, et al. Constitutive activation of peroxisome proliferator-activated receptor-gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells. J Biol Chem 2002; 277(37): 34176–81PubMedGoogle Scholar
  64. 64.
    Ishibashi M, Egashira K, Hiasa K, et al. Antiinflammatory and antiarteriosclerotic effects of pioglitazone. Hypertension 2002; 40(5): 687–93PubMedGoogle Scholar
  65. 65.
    Haffner SM, Greenberg AS, Weston WM, et al. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002; 106(6): 679–84PubMedGoogle Scholar
  66. 66.
    Martens FM, Visseren FL, Lemay J, et al. Metabolic and additional vascular effects of thiazolidinediones. Drugs 2002; 62(10): 1463–80PubMedGoogle Scholar
  67. 67.
    Takagi T, Yamamuro A, Tamita K, et al. Impact of troglitazone on coronary stent implantation using small stents in patients with type 2 diabetes mellitus. Am J Cardiol 2002; 89(3): 318–22PubMedGoogle Scholar
  68. 68.
    Jackson SM, Parhami F, Xi XP, et al. Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction. Arterioscler Thromb Vasc Biol 1999; 19(9): 2094–104PubMedGoogle Scholar
  69. 69.
    Claudel T, Leibowitz MD, Fievet C, et al. Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor. Proc Natl Acad Sci U S A 2001; 98(5): 2610–5PubMedGoogle Scholar
  70. 70.
    Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107: 499–511PubMedGoogle Scholar
  71. 71.
    McTaggart F, Buckett L, Davidson R, et al. Preclinical and clinical pharmacology of rosouvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001; 87(5A): 28B–32BPubMedGoogle Scholar
  72. 72.
    Davidson MH. Rosouvastatin: a highly efficacious statin for the treatment of dyslipidaemia. Expert Opin Investig Drugs 2002; 11(1): 125–41Google Scholar
  73. 73.
    Evans M, Rees A. Effects of HMG-CoA reductase inhibitors on skeletal muscle: are all statins the same? Drug Saf 2002; 25: 649–63PubMedGoogle Scholar
  74. 74.
    Olsson AG, Pears J, McKellar J, et al. Effect of rosuvastatin on low density lipoprotein cholesterol in patients with hypercholesterolaemia. Am J Cardiol 2001; 88: 504–8PubMedGoogle Scholar
  75. 75.
    Davidson M, Ma P, Stein E, et al. Comparison of effects on low density lipoprotein cholesterol and high density lipoprotein cholesterol with rosuvastatin vs atorvastatin in patients with type IIa or IIb hypercholesterolaemia. Am J Cardiol 2002; 89: 268–75PubMedGoogle Scholar
  76. 76.
    Schuster H. Rosuvastatin: a highly effective new 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor: review of clinical trial data at 10–40mg doses in dyslipidemic patients. Cardiology 2003; 99(3): 126–39PubMedGoogle Scholar
  77. 77.
    Stein E. The lower the better?: reviewing the evidence for more aggressive cholesterol reduction and goal attainment. Atheroscler Suppl 2002; 2(4): 19–25PubMedGoogle Scholar
  78. 78.
    Thompson GR. Executive summary of simvastatin. J Drug Eval Cardiovasc Med 2002; 1: 53–88Google Scholar
  79. 79.
    Pazzucconi F, Dorigotti F, Gianfranceschi G, et al. Therapy with HMG CoA reductase inhibitors: characteristics of the long-term permanence of hypocholesterolemic activity. Atherosclerosis 1995; 117(2): 189–98PubMedGoogle Scholar
  80. 80.
    Miettinen TA, Gylling H, Strandberg T, et al. Baseline serum cholestanol as predictor of recurrent coronary events in subgroup of Scandinavian simvastatin survival study. Finnish 4S Investigators. BMJ 1998; 316(7138): 1127–30Google Scholar
  81. 81.
    Naoumova RP, Marais AD, Mountney J, et al. Plasma mevalonic acid, an index of cholesterol synthesis in vivo, and responsiveness to HMG-CoA reductase inhibitors in familial hypercholesterolaemia. Atherosclerosis 1996; 119(2): 203–13PubMedGoogle Scholar
  82. 82.
    Hallikainen MA, Sarkkinen ES, Usitupa MIJ. Plant stanol esters affect serum cholesterol levels of hypercholesterolaemic men and women in a dose dependent manner. J Nutrition 2000; 130: 767–76Google Scholar
  83. 83.
    Catapano AL. Ezetimibe: a selective inhibitor of cholesterol absorption. Eur Heart J 2001; Suppl. E: E6-10Google Scholar
  84. 84.
    Patrick JE, Kosoglou T, Stauber KL, et al. Disposition of the selective cholesterol absorption inhibitor ezetimibe in healthy male subjects. Drug Metab Dispos 2002; 30(4): 430–7PubMedGoogle Scholar
  85. 85.
    Bays HE, Moore PB, Drehobl MA, et al. Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies. Clin Ther 2001; 23: 1209–30PubMedGoogle Scholar
  86. 86.
    Dujovne CA, Ettinger MP, McNeer JF, et al., Esetimibe Study Group. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol 2002; 90(10): 1092–7PubMedGoogle Scholar
  87. 87.
    Ezzet F, Wexler D, Statkevich P, et al. The plasma concentration and LDL-C relationship in patients receiving ezetimibe. J Clin Pharmacol 2001; 41(9): 943–9PubMedGoogle Scholar
  88. 88.
    Heek M, Compton DS, Davis HR. The cholesterol absorption inhibitor, ezetimibe, decreases diet-induced hypercholesterolemia in monkeys. Eur J Pharmacol 2001; 415: 79–84PubMedGoogle Scholar
  89. 89.
    Davis Jr HR, Compton DS, Hoos L, et al. Ezetimibe, a potent cholesterol absorption inhibitor, inhibits the development of atherosclerosis in ApoE knockout mice. Arterioscler Thromb Vasc Biol 2001; 21(12): 2032–8PubMedGoogle Scholar
  90. 90.
    Gagne C, Gaudet D, Bruckert E, et al. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002; 105: 2469–75PubMedGoogle Scholar
  91. 91.
    Gagne C, Bays HE, Weiss SR, et al., Ezetimibe Study Group. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002; 90(10): 1084–91PubMedGoogle Scholar
  92. 92.
    Suckling KE, Stange EF. Role of acyl-CoA: cholesterol acyltransferase in cellular cholesterol metabolism. J Lipid Res 1985; 26(6): 647–71PubMedGoogle Scholar
  93. 93.
    Insull Jr W, Koren M, Davignon J, et al. Efficacy and short-term safety of a new ACAT inhibitor, avasimibe, on lipids, lipoproteins, and apolipoproteins, in patients with combined hyperlipidemia. Atherosclerosis 2001; 157(1): 137–44PubMedGoogle Scholar
  94. 94.
    Kane JP, Havel RJ. Disorders of biogenesis and secretion of lipoproteins containing B apolipoproteins. In: Servier CR, Beaudet AR, Sly WS, et al., editors. The metabolic and molecular basis of inherited disease. New York (NY): McGraw-Hill, 1995: 1853–85Google Scholar
  95. 95.
    Robl JA, Sulsky R, Sun CQ, et al. A novel series of highly potent benzimidazole-based microsomal triglyceride transfer protein inhibitors. J Med Chem 2001; 44(6): 851–6PubMedGoogle Scholar
  96. 96.
    Brown WV. Novel approaches to lipid lowering: what is on the horizon? Am J Cardiol 2001; 87(5A): 23B–7BPubMedGoogle Scholar
  97. 97.
    Brousseau ME, Schaefer EJ. New targets for medical treatment of lipid disorders. Curr Atheroscler Reps 2002; 4: 343–9Google Scholar
  98. 98.
    Tall AR. Plasma cholesteryl ester transfer protein. J Lipid Res 1993; 34: 1255–74PubMedGoogle Scholar
  99. 99.
    Koizumi J, Mabuchi H, Yoshimura A, et al. Deficiency of serum cholesteryl-ester transfer activity in patients with familial hyperalphalipoproteinaemia. Atherosclerosis 1985; 58(1–3): 175–86PubMedGoogle Scholar
  100. 100.
    Okamato H, Yonemori F, Wakitani K, et al. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature 2000; 406: 203–7Google Scholar
  101. 101.
    Asami Y, Yamagishi I, Akyoshi K, et al. Inhibitory effect of TS-962 on the formation of early atherosclerotic lesions in high fat fed hyperlipidaemic hamsters. Atherosclerosis 1999; 146: 237–42PubMedGoogle Scholar
  102. 102.
    De Groot GJ, Kuivenhoven JA, Stalenhoef AF, et al. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705 in humans: a randomised phase II dose response study. Circulation 2002; 105: 2159–65Google Scholar
  103. 103.
    Brooks-Wilson A, Marcil M, Clee SM, et al. Mutations in ABCA1 in Tangier disease and familial high density lipoprotein deficiency. Nat Genet 1999; 22: 336–45PubMedGoogle Scholar
  104. 104.
    Joyce CW, Amar MJ, Lambert G, et al. The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apo E knockout mice. Proc Natl Acad Sci U S A 2002; 99: 407–12PubMedGoogle Scholar
  105. 105.
    Repa JJ, Turley SD, Lobarco JA, et al. Regulation of absorption of and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 2000; 289: 1524–9PubMedGoogle Scholar
  106. 106.
    Brousseau ME. HDL cholesterol: third annual international conference on metabolic pathways and drug development. IDrugs 2002; 5: 327–30PubMedGoogle Scholar
  107. 107.
    Davidson MH, Dicklin MR, Maki KC, et al. Colesevelam hydrochloride: a non absorbed cholesterol lowering agent. Expert Opin Investig Drugs 2000; 9: 2663–71PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Marc Evans
    • 1
  • Aled Roberts
    • 2
  • Steve Davies
    • 2
  • Alan Rees
    • 2
  1. 1.Department of Metabolic Medicine, Diabetes and EndocrinologyUniversity of Wales College of MedicineCardiffWales
  2. 2.Department of Metabolic Medicine, Diabetes and EndocrinologyUniversity Hospital of WalesCardiffWales

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